DESCRIPTION: The nervous system is composed of an integrated network of neurons and synaptic connections. To function properly the nervous system requires neuronal cells and their axons to be correctly positioned at a precise time. To accomplish this, cells sample the surrounding environment and are guided by a variety of long and short range cues. One long range guidance cue, netrin- 1, functions in both axonal attraction and repulsion. Attraction is mediated through the netrin-1 receptor, DCC, and repulsion through a receptor complex of DCC and UNC5H. Recently, a second function involving apoptosis has begun to emerge for the netrin-1 receptors. I propose to understand how cells distinguish between guidance and apoptosis by investigating the mechanism by which UNC5H1 relays the apoptotic signal into the cell and identifying molecules downstream of UNC5H1. UNC5H1 may be a central link between the cellular processes of axon guidance and apoptosis during development and depending on the state of the cell, a disruption in UNC5H1 could affect either of these cellular processes resulting in various neurological disorders.